Method to obtain microparticles

ABSTRACT

A method for the preparation of homogeneous microparticles containing a pharmaceutically active substance by a spray freezing technique wherein the medium to be atomized into droplets has a high dry content and comprises besides the active substance a polymer and a liquid (in which the polymer may be soluble) in which the active substance and polymer are suspended, dissolved or emulsified.

FIELD OF INVENTION

[0001] The present invention provides a method of obtainingmicroparticles by a spray freezing technique. More specifically thepresent invention relates to a method by which spherical microparticlescontaining one or more pharmaceutically active substances can beprepared.

BACKGROUND OF THE INVENTION

[0002] The strategy for pharmaceutical formulation of a given drugdepends on different factors. Ultimately, these factors emanate from 1)the therapeutic needs, 2) the physical chemical properties of the drug,and 3) the influence of the biological environment where the formulationwill release its contents. Thus, both technical and biopharmaceuticalconsiderations will contribute to a successful therapy.

[0003] However, improved drug administration may also be achieved by socalled modified release of the drug, which has been discussedextensively in the literature, e g R L Langer and D L Wise (Eds)“Medical Applications of Controlled Release”, vols I, II (1984), CRCPress Inc, Boca Raton.

[0004] Several approaches to achieve different types of modified releaseare described in the references above. Of special importance to thepresent invention is modified release achieved by formulating the activesubstance with a suitable carrier material in the form ofmicroparticles. Such a formulation then contains multiparticulatediscrete delivery units, each of which can be coated if necessary with,e g a suitable pH sensitive, semipermeable or other polymeric film.Several advantages can be obtained with this type of formulationcompared with more conventional delivery means. Thus, the small size ofthe microparticles assures a fast and predictable emptying from thestomach, which is of special importance in the presence of food.Further, the particles will spread over a larger area in the wholeGI-tract compared with a conventional monolithic (single-unit)formulation. This will result in a safer therapy when the activesubstance has local irritating side effects. Controllable plasma levelsof absorbed drug can also be obtained. The microparticle formulationwill also have a longer residence time in the colon which makes 24 hrsextended release formulations possible. From a technological point ofview, microparticles are more suitable for coating and handling since atechnical fault during the process may be serious for single unitformulations but less so for micropellets. Also, microparticleformulations are more easily manufactured and prepared in differentdoses than standard tablet systems.

PRIOR ART

[0005] An ideal method for the preparation of microparticles where thedrug is homogeneously distributed within a polymeric matrix, should besimple, reproducible, rapid and minimally dependent on the solubilitycharacteristics of the drug. A high product yield and a high degree ofretention of the active substance in the final microparticles shouldalso be obtained.

[0006] Several different techniques are available for makingmicroparticles (<1 mm), e g spray-drying, extrusion-spheronization,spray-chilling, emulsion solvent evaporation/extraction and coating ofnonpareil spheres, among others. A recent review was presented by Contiet al in STP Pharma Sci 7, 331 (1997) where the technical aspects ofcoacervation, spray-drying, emulsion solvent extraction, and emulsionsolvent evaporation were discussed.

[0007] However, all existing techniques suffer from one or moredrawbacks. Thus, many drugs are sensitive to heat and therefore willdeteroriate which restricts the use of spray-drying or spray-chilling.

[0008] In extrusion spheronization and in coating of non-pareilsparticles it has been difficult to achieve acceptable microparticles inthe size range of 50-400 μm. Pellets made by these methods containsignificant amounts of inert excipients. This may make the pelletizationof high-dose drugs by these methods a difficult task.

[0009] Finally, in emulsification solvent evaporation, an emulsion hasto be made and the drug to be incorporated is preferably lipophilic,which restricts the drugs which can be used. Another drawback is thetoxicity of the solvent used, usually methylene chloride, which canremain in the microparticles after drying.

[0010] However, despite the many different approaches there has not beendisclosed a technique that can produce both smaller microparticles butalso particles of more uniform size. It is important to avoid, e gsegregation and dose variation during further processing into capsulesor tablets. Further, the existing techniques do not incorporate severaldesirable aspects such as the possibility to produce sphericalmicroparticles of different size ranges that are homogeneous, have ahigh drug content and sufficient mechanical strength (to e g withstandcoating processes) into one single technique.

[0011] A spray-freezing technique has been used for the processing andgranulation of ceramic materials to achieve homogeneous distribution ofadditives within granules to be compacted. For the processing ofslurries containing silicon-nitride, sintering additives and a binder,spherical free-flowing granules have been prepared by spray-freezing andsubsequent freeze-drying. The homogenity of the slurry was retained inthe granules and thus in the final sintered product (Nyberg et al,Euro-Ceramics II 1, 447 (1993)). Suspensions of silicon carbide andadditives were processed in this way to give granules for compaction(U.S. Pat. No. 4,526,734). The increased homogenity compared withtraditional granulation techniques resulted in better mechanicalproperties of a whisker reinforced ceramic (EP 0 584 05 1). The processis also feasible. for making homogeneous powder blends for ceramicsuperconductors (Japanese unexamined patent application no. 59-102433).

[0012] Normally pharmaceutical materials are lyophilized byfreeze-drying in a bulk process in which the solution/suspension to befreezed is placed in vials or on trays in a freeze-drier, where freezingand subsequent sublimation of the dry solvent take place. The driedproduct is a powder cake.

[0013] The rapid freezing provided by spray-freezing ensures that noconcentration gradients exist in the resulting frozen particles anddegradation of biological material is prevented. This approach has beenused to achieve precise metering and dispensing (M J Akers and D JSchmidt, BioPharm 28, (April 1997)); where the frozen particles were inthe form of large lumps of size 1-9 mm. Freezing of droplets in a movingbath of Freon 12 (−20° C.), which medium conflicts with environmentaldemands, has been used to obtain porous, free-flowing, sphericalgranules with rapid dissolution (U.S. Pat. No. 3,932,943); as well asmaking homogenous granules for tableting with precise dosing (U.S. Pat.No. 3,721,725).

[0014] A process for preparing foamed bioabsorbable polymer particlesfor surgical use was presented in U.S. Pat. No. 5,102,983. Here,however, the porosity was very large, and the pore sizes in the range of4-10 μm, the dry content of the solution being sprayed being 1-20 wt %.

[0015] U.S. Pat. No. 5,019,400, disclosed the use of a mixture of abiologically active material, a polymer, and a solvent which was sprayedinto a non-solvent cooling medium that freezed the droplets withsubsequent extraction of the solvent in the droplets during heating. Theparticles were finally dried in a vacuum-drier. The microparticlesformed were porous, and contained 0.01-50 % of the active substance. Thedry content of the solution sprayed was 6wt %. This process is notentirely satisfactory since it is an advantage to have one single dryingstep after freezing and also a higher active substance content than 50wt % in order to make high dose materials.

[0016] U.S. Pat. No. 5,405,616 discloses a method of forming droplets byforcing a suspension/solution/emulsion through calibrated jets. Thedroplets then fall into liquid nitrogen. Due to low shear forces thesize of the pellets formed is large; 0.2-12 mm, which would then give aless safe dosability than if smaller particles could have been achieved.The smallest particles achieved were 0.8-1 mm. Further, to achieve lowfriability pellets, the drying step after freeze-drying was performed bythawing the pellets before conventional vacuum drying. To achieve theselow friability pellets the matrix former is restricted to materials thatduring thawing will form a gel. The particles obtained contain no morethan 33 wt % of the active substance.

[0017] To the skilled person particle production utilizing the techniquedescribed in U.S. Pat. No. 5,405,616 appears to be quite a slow processand not suitable for large scale industrial pharmaceutical production.

OBJECT OF THE INVENTION

[0018] An object of the present invention is to provide a method for theproduction of microparticles. More specifically, the method is for theproduction of homogeneous microparticles which does not have thedrawbacks of the methods discussed above, e.g. methods that rely on heator multiple solvents for drug dissolution, but instead puts norestrictions on the drug to be incorporated. A further object is toprovide a method for the production of microparticles with controllableamounts of incorporated drug in a high-yield process. Also, theinvention provides a method to produce homogeneous microparticles withan incorporated drug that have low friability so that they for instancecan withstand coating processes. A further object of the invention is toprovide a method to produce microparticles that have easily controllabledensity and strength. A further object is to obtain microparticles witha high content of active substance.

DISCLOSURE OF THE INVENTION

[0019] It has now been found that free-flowing, homogeneousmicroparticles having low friability can be obtained by spray-freezing asuspension, solution or emulsion of a pharmaceutically active substancewith subsequent freeze-drying of the frozen microparticles. Themicroparticles are preferably spherical in shape. The porosity of themicroparticles obtained is controlled in the process by the dry contentof the suspension, solution or emulsion. Apart from the porosity, thebrittleness of the microparticles is controlled by the amount of polymerbinder included in the suspension, solution or emulsion. In order toobtain low friability particles the dry content of the suspension orsolution or emulsion should be high.

[0020] Generally the following conditions are applicable to obtain lowfriability microparticles according to the method of the invention;

[0021] Low friability microparticles that can for instance withstandcoating with a polymeric film, are achieved when the suspension,solution or emulsion has a dry volume content of at least 15 vol %,preferably up to 60 vol %, and a polymer binder content of at least 5weight %, preferably 10 weight % or more, and more preferably 15 weight% or more (based upon dry content). A high total pharmaceutically activesubstance content can be obtained by using the present invention, suchas up to 95 weight % or preferably 90 weight % (based upon dry content).The median pore size of the microparticles obtained being preferably amaximum of 1.0 μm. Dry content and dry volume content are weight % andvolume %, respectively, of dry material in thesuspension/solution/emulsion (dry/(dry+liquid)), wherein the drymaterial is pharmaceutically active substance+polymer.

[0022] According to the present invention homogenous low friabilitymicroparticles can be obtained when the dry content is from 15 to 60 vol% and the polymer binder content is 5 weight % or more giving drymicroparticles with a relative density of 15 to 60 % (a porosity of 85down to 40 vol %). [Relative density: weight of freeze-driedmaterial/volume of freeze-dried material/theoretical density of drymaterial].

[0023] The content of the pharmaceutically active substance calculatedon the weight of the dried microparticles may be from 60 to 95 weight %,preferably from 75 to 90 weight %.

[0024] The dry content of the liquid medium is defined as the residueafter drying at 110° C. for 2 hours, divided by the total amount beforedrying. The dry content can be expressed either as weight percent or,preferably, as volume percent.

[0025] The success in obtaining low porous microparticles and thus lowfriable microparticles depends on the volume fraction of dry materialand the amount of polymer binder. The dry content of asuspension/solution/emulsion should thus preferably be expressed as avolume fraction although this cannot always be calculated.

[0026] The microparticles may be obtained by spraying a homogeneoussuspension, solution or emulsion of the active subtance(s) through anatomizer into a vessel with a cold medium with a temperature well belowthat of the freezing point of the liquid in the droplets. Frozendroplets will then form instantaneously. The structure of thesuspension, solution or emulsion is retained in the droplets providing ahomogeneous distribution of the substances within the droplets. Thefrozen liquid is then sublimated by freeze-drying of the frozen dropletswhere the structure of the droplets is retained due to lack of migrationof substances during drying.

[0027] The following general steps of the procedure are furtherexemplified in the Experimental Section below:

[0028] a) Preparation of a medium for atomizing. The medium is asuspension, a solution or an emulsion of the active substance. Asuspension may be prepared by dissolving or dispersing a polymer in aliquid (as defined below), and then adding fine particles of the activesubstance. A further dispersing agent (typically in an amount of lessthan 20% (w/w) of the polymer amount) might also be included tofacilitate the dispersion of the active substance. The polymer mightthen act as a binder between the fine active substance particles in themicroparticles and can be either a water soluble or a non-water solublepolymer, according to definitions below.

[0029] b) Atomizing of the suspension/solution/emulsion into droplets.The suspension, solution or emulsion is fed by e.g. a peristaltic pumpthrough a nozzle that could be a pneumatic nozzle, an ultrasonic nozzle,a rotary atomizer or a pressurized nozzle. A typical size distributionof spheres produced by this process can range from 1000 μm down to 10μm.

[0030] c) Freezing of the formed droplets: The atomizer is situatedabove the cold medium in a cylindrical vessel. If the cold medium is aliquified gas the droplets in the spray formed by the nozzle hit thecold boiling gas before hitting the cold medium that is stirred to get abetter wetting of the droplets. Instant freezing takes place and thestructure of the homogeneous suspension is retained within the frozenmicroparticles.

[0031] d) Sublimation of the frozen liquid within the droplets: Thefrozen droplets are transferred from the cold medium to a freeze-drierto sublimate the frozen liquid. This step takes place without anyshrinkage of the droplets or migration of excipients ( e g polymers) andthus the structure of the suspension/solution/emulsion is retainedwithin the dry microparticles.

[0032] The polymer or dispersing agent used for the formulation may be adry polymer that is partly or fully soluble in the liquid. The polymeror dispersing agent used might also be a dispersion of polymer particles(e g a latex).

[0033] The polymer or dispersing agent could be but are not limited tothe excipients listed below.

[0034] cellulose derivatives, like ethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethylhydroxyethyl cellulose, carboxymethyl cellulose, cellulose acetatebutyrate, cellulose acetate phtalate, methylcellulose, etc

[0035] other polysaccharides, like alginate; xanthan; carrageenan;scleroglucan; pullulan; dextran; hyaluronic acid; chitin; chitosan;starch; etc

[0036] other natural polymers, like proteins (e g albumin, gelatin,etc); natural rubber; gum arabic; etc

[0037] synthetic polymers, like acrylates (e g polymethacrylate,poly(hydroxy ethyl methacrylate), poly(methyl methacrylate),poly(hydroxy ethyl methacrylate-co methyl methacrylate), Carbopolg 934,etc); polyamides (e g polyacrylamide, poly(methylene bisacrylamide),etc); polyanhydrides (e g poly(bis carboxyphenoxy)methane, etc); PEO-PPOblock-co-polymers (e g poloxamers, etc); polyvinyl chloride; polyvinylpyrrolidone; polyvinyl acetate; polyvinyl alcohol; polyethylene,polyethylene glycols and co-polymers thereof; polyethylene oxides andco-polymers thereof; polypropylene and co-polymers thereof; polystyrene;polyesters (e.g. poly(lactic acid), poly(glycolic acid),poly(caprolactone), etc, and co-polymers therof, and poly(ortho esters),and co-polymers thereof; polycarbonate; cellophane; silicones (e.g. poly(dimethylsiloxane), etc); polyurethanes; synthetic rubbers (e.g. styrenebutadiene rubber, isopropene rubber, etc); etc

[0038] surfactants, e.g. anionic, like sulphated fatty alcohols (e gsodium dodecyl sulphate), sulphated polyoxyethylated alcohols orsulphated oils, etc; cationic, like quaternary ammonium and pyridiniumcationic surfactants, etc; non-ionic, like polysorbates (e.g. Tween),sorbitan esters (e.g. Span), polyoxyethylated linear fatty alcohols(e.g. Brij), polyoxyethylated castor oil (e g Cremophor),polyoxyethylated stearic acid (e g Myrj), etc.

[0039] other substances, like shellacs; waxes (e.g. carnauba wax,beeswax, glycowax, castor wax, etc); nylon; stearates (e.g. glycerolpalmitostearate, glyceryl monostearate, glyceryl tristearate, stearylalcohol, etc); lipids (e g glycerides, phospholipids, etc); paraffin;lignosulphonates; etc.

[0040] Also, combinations of these excipients are possible.

[0041] The excipients mentioned above can be toughened by introducing aplasticizer. The plasticizer can be but is not limited to theplasticizers mentioned below.

[0042] glycerin, polyethylene glycol, propylene glycol, triethylcitrate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate,sorbitol, triacetin, etc

[0043] Also, combinations of these plasticizers are possible.

[0044] The liquid used for the preparation of thesuspension/solution/emulsion, can be a solvent for the excipients listedabove and encompass, e g water or organic solvents with freezing pointswell above the freezing point of the medium used for freezing asexemplified below. Liquids, alone or a mixture of, suitable to make asuspension/solution/emulsion of the active substance, can then be, butare not limited to:

[0045] water (melting point (mp) 0° C.), tertiary butyl alcohol (mp25.5° C.), cyclohexane (mp +6° C.), methylene chloride (mp −95.1° C.),acetone (mp −95.3° C.), methanol (mp −94° C.), ethanol (mp −117° C.),etc;

[0046] The cold medium can typically be a liquified gas, e.g. liquidnitrogen (boiling point −196° C.), liquid argon (boiling point −186°C.), liquid oxygen (boiling point −183° C.), or a cooled solvent wellbelow the freezing point of the liquid in the suspension.

[0047] The mechanical strength of the microparticles is important fordetermining whether they will withstand processing with a polymercoating in a fluid bed.

[0048] Examining the microparticles with a microscope before and afterthe fluidization in a fluid bed will give an indication of theirmechanical strength.

[0049] To achieve a relative measurement of mechanical strength thepressure where microparticles started to deform was evaluated.Microparticles within a certain size range (sieve fraction) were placedas a monolayer onto the surface of a probe with a certain area.Different loads (forces) were applied to the layer of microparticles forone minute.

[0050] Examination of the monolayer of microparticles before and afterloading was made in a Scanning Electron Microscope to see at what loadthe microparticles started to deform. The pressure at which themicroparticles started to deform was then calculated.

[0051] Pharmaceutically active substances suitable to formmicroparticles of this invention can be but are not limited to peptides,proteins, low molecular organic substances, pro-drugs, antigens,hormones.

[0052] Thus, a microparticle according to the present inventioncomprises one (or several) pharmaceutically active substances with oneor several additional non-active substances, which are dispersed withinthe microsphere.

[0053] Uncoated particles can be retrieved as they are easily dissolvedwhen they are immersed into a liquid due to their porous structure.

[0054] The microparticles obtained can be coated with a polymer toachieve either a time-controlled release, a site-controlled release or apH-dependent release. Suitable polymers for coating can be, but are notlimited to, the same type of polymers as listed above.

[0055] The coated microparticles can be put into capsules orincorporated into a tablet compressed by methods known by those skilledin the art.

[0056] The formulations produced based on the microparticles, coated oruncoated, can be given by different administration routes, such as, butnot limited to, the oral, the parenteral, the nasal, the pulmonary, therectal, the tonsillar, the buccal, the intraocular, the vaginal etc,administration routes. The preferred administrations are by the oral,nasal, pulmonary and rectal routes.

[0057] Working Examples

[0058] The following examples illustrate different aspects of theinvention.

[0059] The size distribution of the obtained microparticles was measuredby sieving. By mercury porosimetry measurements the bulk-density andpore-size distributions were determined. To determine the median poresize the pressure range for mercury intrusion corresponded to pore sizesbetween 0.0005 μm and 10 μm.

[0060] By subjecting a monolayer of the microparticles to compactionforces their relative strength was measured.

EXAMPLE 1

[0061] Preparation of Microparticles with a High Loading of Dry Contentthat Withstand Coating in a Fluidized Bed

[0062] A suspension containing talc powder was made according to thecomposition below; Talc powder (1-2 μm)  90 g Talc powder (5-80 μm) 210g HPMC, 6 cps  80 g Tween 80 (polysorbate 80)  6 g Purified water 750 g

[0063] First, polysorbate 80 was mixed with the water. The HPMC was thenadded and dissolved during stirring with subsequent addition of thesubstance. The suspension was then deagglomerated by high-shear mixing.The deagglomerated suspension was fed through a pneumatic nozzle with adiameter of 1.0 mm at a speed of about 15 ml/min. The pressure of theatomizer was 1 bar. The spray formed first hit the cold gas above theliquid in a vessel filled with liquid nitrogen that was stirred to get abetter wetting and instantaneous freezing of the droplets. The frozendroplets have a higher density than liquid nitrogen which make them sinkto the bottom of the vessel. The frozen droplets/microparticles werethen placed in a conventional freeze-drier with a shelf-temperature of−20° C. The primary drying was performed stepwise at −20° C. to 0° C. at0.1 mbar. The dry microparticles were free-flowing and spherical.Scanning Electron Microscopy showed a homogeneous distribution of thetalc powder with pores (0.1-2 μm) in between. The bulk density, medianpore size and mechanical strength was measured and the results are shownin table 2.

[0064] Compaction measurements showed that the microparticles obtainedhad a low friability (high mechanical strength).

[0065] Fluidization of the microparticles in Example 1 in a fluidizedbed showed by microscopy that the microparticles did not break down.These microparticles started to deform at a pressure of 94 kPa (sievefraction: 450-630 μm). Final coating with a polymer in a fluidized bedproved that the microparticles could be successfully coated.

EXAMPLE 2

[0066] Coating of Microparticles with a Polymeric Film

[0067] The microparticles from Example 1 were easily handled withoutfalling apart and tough enough to be successfully coated. A fraction of20 g of the microspheres, 150-300 μm in size, were successfully coatedwith an enteric polymer to a film thickness of 30 μm, in a fluidizedbed.

[0068] Characterization of Pellets Obtained in Example 1. TABLE 1 Sizedistribution. Sieving (weight fraction %) Fraction Example 1 <100 μm 1100-150 μm 2 150-300 μm 22 300-450 μm 32 450-630 μm 26 630-800 μm 12800-1000 μm 4

[0069] TABLE 2 Characterization of microparticles Mercury porosityBinder measurements (wt %) Pore median based on size (μm) Dry contentdry Bulk density (measured Mechanical strength Example no. (vol %)content (g/cm³) range: 0.0005-10 μm) Kpa Fraction 1 19.2 21 0.47 0.8 94450-630 μm

1. A method of preparing homogeneous microparticles containing apharmaceutically active substance by use of a spray freezing techniquewhich method comprices atomizing into droplets a liquid medium having aminimum dry content of 15% by volume and comprising a) apharmaceutically active substance, b) a polymer selected from the groupconsisting of water soluble polymers and non-water soluble polymers,said polymer being present in an amount of at least 5 per cent by weightbased upon the dry content of the medium, c) a liquid in which thepharmaceutically active substance and polymer are suspended, dissolvedor emulsified, and d) optionally a dispersing agent, selected from thegroup consisting of polymers, surfactants, other substances and mixturesthereof, freezing the formed droplets and sublimating the frozen liquidof the droplets to obtain dry, homogeneous microparticles.
 2. A methodaccording to claim 1, wherein the polymer of the liquid mediumconstitutes 10 weight % or more of the dry content.
 3. A methodaccording to claim 1, wherein the polymer of the liquid mediumconstitutes 15 weight % or more of the dry content.
 4. A methodaccording to claim 1 wherein the dry content of the liquid medium isfrom 15 to 60 vol %.
 5. A method according to claim 1, wherein the dryvolume content of the liquid medium is from 15 to 60 vol % and gives drymicroparticles with a relative density of 15 to 60 %.
 6. A methodaccording to claim 1, wherein the dry volume content of the liquidmedium is from 15 to 60 vol % and gives dry microparticles with aporosity of 85 down to 40 vol %.
 7. A method according to claim 1wherein the liquid medium to be spray-freezed is a suspension.
 8. Amethod according to claim 1 wherein the liquid medium to bespray-freezed is a solution.
 9. A method according to claim 1 whereinthe liquid medium to be spray-freezed is an emulsion.
 10. A methodaccording to any of the preceding claims wherein the content of thepharmaceutically active substance is from 60 to 95 weight %, preferably75 to 90 weight %, of the weight of the dried microparticles.
 11. Amethod according to any of the preceding claims wherein the dry contentof the medium is from 15 to 60 vol % and with the content of thepharmaceutically active substance being from 60 to 95 weight % of thedried microparticles.
 12. A method according to any of the precedingclaims wherein the polymer is selected from the group consisting of acellulose derivative, a polysaccharide, a natural polymer, a syntheticpolymer, a surfactant and mixtures thereof.
 13. A method according toany of the preceding claims wherein the dispersing agent is selectedfrom the group consisting of polymers, surfactants, other substances andmixtures thereof.
 14. A method according to any of the preceding claimswherein the liquid in which the polymer is soluble is selected from thegroup consisting of water, tertiary butyl alcohol, cyclohexane,methylene chloride, methanol, ethanol and mixtures thereof.
 15. A methodaccording to any of the preceding claims wherein the cold medium isselected from the group consisting of liquid nitrogen, liquid argon,liquid oxygen or a cooled solvent well below the freezing point of theliquid in the suspension.
 16. A method according to any of the precedingclaims wherein the sublimation is performed by freeze-drying.
 17. Amethod according to any of the preceding claims wherein the sizedistribution of the prepared microparticles are in the range from 10 to1000 μm.
 18. Microparticles when prepared according to the method of anyof claims 1-17.
 19. The microparticles according to claim 18 furthercomprising a polymeric film coating.
 20. A method of preparinghomogenous microparticles containing a pharmaceutically activesubstance, the particles being coated with a polymer film coating, whichmethod comprises a method as claimed in any one of claims 1-17 followedby coating the microparticles with a polymeric film coating.